Project Summary/Abstract : A characteristic of activated glial cells is the increased expression of the peripheral benzodiazepine receptor (PBR). As glial cells are activated in a variety of cerebral disorders with associated brain injury, PBR binding is considered to be a useful marker of brain injury. The PBR ligand that has been used most frequently for brain imaging studies with positron emission tomography (PET) is [11C]-R-PK11195. In a previous study with [11C]-R- PK11195, our group had found that in comparison to control subjects, there was increased PBR binding in patients with HIV associated dementia (HAD). Although the finding showed that increased glial activity in HAD can be measured with PET, increased glial activity was not found in all expected regions. Furthermore, there were no distinguishable differences in glial activity between HIV nondemented (HIV-ND) subjects and HAD subjects. However, there was a trend showing that HIV-ND subjects had a PBR binding level that was intermediate between HAD and control subjects. A similar [11C]-R-PK11195 study by Wiley and colleagues at the University of Pittsburgh showed no significant increase in PBR binding in HIV subjects. We believe that the difficulty in achieving more conclusive results is partly due to the chemical and pharmacokinetic properties of PK11195 that make it a non-ideal PET ligand. In particular, PK11195 has high nonspecific binding, binds to plasma proteins extensively, and has low brain uptake. Thus there is a definite need for a better ligand to examine PBR binding and glial activation. Recently, a new PBR ligand known as [11C]DPA-713 has been developed in the laboratory of Dr. Michael Kassiou. As compared with [11C]-R-PK11195, which has a logP of 3.4, DPA-713 has a smaller logP of 2.4, which indicates that DPA-713 is less lipophilic than PK11195 and should have less nonspecific binding. [11C]DPA-713 also binds to PBR with higher affinity (4.7 nM), than does [11C]-R-PK11195 (9.3 nM). A baboon PET study has confirmed that [11C]DPA-713 has highly specific brain uptake. A recent study in a rat model of neuroinflammation shows that [11C]DPA-713 provides better image contrast than [11C]-R-PK11195. Attesting to the promise of this compound, at our request the NIMH has completed a toxicology package, performed by SRI International, so that DPA-713 will be translatable for use in the clinic. Here we propose to do the first-in-man study with [11C]DPA-713. Methodology will be developed to achieve reliable quantification of PBR binding with [11C]DPA-713. In addition, HIV patients will be studied to determine if [11C]DPA-713 PET can demonstrate significant differences in PBR binding between controls, HIV- ND, and HAD subjects. Since the initial application, we have invested in a GMP synthesis procedure for [11C]DPA-713, and have recently received approval for these studies from the Johns Hopkins IRB. We have begun scanning human subjects and the results thus far indicate that [11C]DPA-713 has much better brain uptake than [11C]-R-PK11195, and provides better contrast across brain regions.